Robust Antitumor Effects of Combined Anti-CD4-Depleting Antibody and Anti-PD-1/PD-L1 Immune Checkpoint Antibody Treatment in Mice

  • Cancer Immunol Res. 2015 Jun;3(6):631-40. doi: 10.1158/2326-6066.CIR-14-0190.
Satoshi Ueha  1 ,  Shoji Yokochi  2 ,  Yoshiro Ishiwata  2 ,  Haru Ogiwara  1 ,  Krishant Chand  1 ,  Takuya Nakajima  1 ,  Kosuke Hachiga  2 ,  Shigeyuki Shichino  1 ,  Yuya Terashima  1 ,  Etsuko Toda  1 ,  Francis H W Shand  3 ,  Kazuhiro Kakimi  4 ,  Satoru Ito  2 ,  Kouji Matsushima  5
Affiliations
  • 1. Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 2. Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. IDAC Theranostics, Inc., Tokyo, Japan.
  • 3. Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Victoria, Australia.
  • 4. Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo, Japan.
  • 5. Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. [email protected].
PMID: 25711759 DOI: 10.1158/2326-6066.CIR-14-0190
Abstract

Depletion of CD4(+) cells in tumor-bearing mice has strong antitumor effects. However, the mechanisms underlying these effects and the therapeutic benefits of CD4(+) cell depletion relative to other immunotherapies have not been fully evaluated. Here, we investigated the antitumor effects of an anti-CD4-depleting mAb as a monotherapy or in combination with immune checkpoint mAbs. In B16F10, Colon 26, or Lewis lung carcinoma subcutaneous tumor models, administration of the anti-CD4 mAb alone had strong antitumor effects that were superior to those elicited by CD25(+) Treg depletion or other immune checkpoint mAbs, and which were completely reversed by CD8(+) cell depletion. CD4(+) cell depletion led to the proliferation of tumor-specific CD8(+) T cells in the draining lymph node and increased infiltration of PD-1(+)CD8(+) T cells into the tumor, with a shift toward type I immunity within the tumor. Combination treatment with the anti-CD4 mAb and immune checkpoint mAbs, particularly anti-PD-1 or anti-PD-L1 mAbs, synergistically suppressed tumor growth and greatly prolonged survival. To our knowledge, this work represents the first report of robust synergy between anti-CD4 and anti-PD-1 or anti-PD-L1 mAb therapies.

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